Time to redefine HHV-8 MCD and KICS criteria?

TO THE EDITOR:

We read with interest the recently published article by Ramaswami et al¹ titled “Characteristics and outcomes of Kaposi sarcoma herpesvirus (KSHV)–associated inflammatory cytokine syndrome (KICS).” This work provides a comprehensive description of a newly recognized KSHV/human herpesvirus 8 (HHV-8)–related entity, and we commend the authors for their valuable contribution to the field.

KICS is a heterogeneous entity defined by clinical, biological, and radiological criteria that requires the exclusion of KSHV/HHV-8–associated multicentric Castleman Disease (MCD).² Diagnosis of KSHV/HHV-8–associated MCD is based on histological findings, including the presence of mixed or plasma cell Castleman changes with KSHV-infected plasmablasts, also known as KSHV-infected viroblasts (KIVs).^3,4 KIVs have also been detected in effusions, where they are called lambda-restricted plasmablasts (LRPs),⁵ and in the peripheral blood mononuclear cells of patients with MCD flares (reported by de Frémont et al⁶). Peripheral blood mononuclear cells were separated using Ficoll gradient, and a whole blood method is under development. In the study by Ramaswami et al,¹ patients with detectable KIVs/LRPs in their effusions were removed from the analysis depending on whether they had MCD.

We believe this exclusion warrants further discussion. As pointed earlier, MCD diagnosis remains defined by pathological aspects. The diagnostic value of KIV/LRP detection, especially in peripheral blood, has not been fully evaluated in the context of KICS. To explore this, we phenotyped the peripheral blood of 7 patients from our French cohort, who met KICS criteria. We detected KIVs in 5 of 7 (71%, see figure), indicating that peripheral blood analysis can significantly increase the number of patients with detectable KIVs/LRPs within the KICS population.

Clinical and biological phenotype of patients with KSHV/HHV-8-associated inflammatory cytokine syndrome. (A) Clinical and biological characteristics of 7 patients with KICS; (B-D) phenotype of circulating KIVs detected by standard flow cytometry. (B) Gating strategy used to identify circulating KIVs by selecting IgM⁺CD38⁺ cells among CD3^–CD14^– double-negative population (P1). (C) K and λ light-chain staining among the IgM⁺CD38⁺ population. (D) Percentage of CD19, CD20, CD27, CD40, CD86, and CD24 expression among circulating KIVs (IgM⁺CD38⁺λ⁺) in peripheral blood (n = 5). §, The presence of lymph nodes was assessed by clinical examination and contrast-enhanced computed tomography. “-” means absence of pathological lymphadenopathy, whereas “+” means that pathological lymphadenopathy was present, but the biopsy showed no aspects of MCD. CRP, C-reactive protein; F, female; IgM, immunoglobulin M; M, male; P, patient.

These findings challenge the distinction between MCD and KICS, suggesting a potential nosological continuum between the 2 disorders, which may share a common pathophysiological process. The detection of LRPs/KIVs in blood and/or effusions should be discussed as a novel biomarker participating in the definition of both MCD and KICS. Further research is needed to better define the spectrum of KIV/LRP–associated disorders.

Conflict-of-interest disclosure: The authors declare no competing financial interests.